Clinical Activity with Brentuximab Vedotin in Cutaneous T .... Prince… · Disclosures Co-funded...

Clinical Activity with Brentuximab Vedotin in

Cutaneous T-cell Lymphoma

- Updated analysis -

- Time to next treatment -

- Disease Stages/Compartments -

- CD30 Expression Level -

Disclosures

Co-funded by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary

of Takeda Pharmaceutical Company Limited, and Seattle Genetics, Inc., Bothell, WA, USA

H. Miles Prince: Advisory board member for Millennium/Takeda Pharmaceuticals; has received

honoraria for advisory boards and research funding for clinical trials

Full disclosure information for all authors is available on request

Brentuximab vedotin was far superior to physician’s choice, demonstrating improved ORR4 (56% vs 13%; p<0.0001),

CR rate (16% vs 2%; adjusted p=0.0046), and PFS (16.7 vs 3.5 months; HR=0.270, 95% CI: 0.169, 0.430; adjusted

p<0.0001), and a reduction in patient-reported symptoms (Skindex-29 symptom domain; –27.96 vs –8.62; adjusted

p<0.0001)1,2

Safety data were consistent with the established tolerability profile1,2

1. Kim YH, et al. Blood 2016;128:182

2. Prince HM, et al. Lancet 2017;390:555–66

ALCANZA: A phase 3, randomized study comparing the efficacy and safety of

brentuximab vedotin versus physician’s choice in CD30-positive MF or pcALCL

CI, confidence interval; CR, complete response; HR, hazard ratio; IV, intravenous; ORR4, overall rate of

responses lasting ≥4 months; PFS, progression-free survival; PO, orally

Inclusion:

• Diagnosis of CD30-positive MF or

pcALCL

– ≥10% CD30-positive on either

neoplastic cells or lymphoid infiltrate

by central review of ≥1 biopsy (≥2

required for MF)

• MF patients with ≥1 prior systemic

therapy

• pcALCL patients with prior

radiotherapy or ≥1 prior systemic

therapy

Exclusion:

• Progression on both prior

methotrexate and bexarotene

Screening*

Ran

do

miz

ati

on

Methotrexate: 5–50 mg PO, weekly

or

Bexarotene: 300 mg/m² (target dose)

PO, daily

Brentuximab vedotin:

1.8 mg/kg IV, every 3 weeks

Up to 48 weeks (16 x 21-day cycles)End of

treatment

visit

Post-

treatment

follow-up

Every 12

weeks for

2 years and

then every

6 months

thereafter

30 days

after last

dose of

study drug

*Within 28 days of randomization

• Methotrexate or bexarotene was managed as standard of care, targeting maximum tolerated effective dose

• International study of 52 centers, 13 countries

ALCANZA: Key efficacy and safety data1

ALCANZA met its primary endpoint: the proportion of patients achieving an objective global response

lasting ≥4 months was 56.3% with brentuximab vedotin versus 12.5% with physician’s choice

(between-group difference = 43.8% [95% CI, 29.1–58.4; p<0.0001])

1. Prince HM, et al. Lancet 2017;390:555–66.

Maximum percentage change in skin mSWAT score PFS (assessed by independent review; ITT)

Bex, bexarotene; CI, confidence interval; ITT, intention-to-treat; mSWAT, modified Severity-

Weighted Assessment Tool; MTX, methotrexate; PFS, progression-free survival; RR, response

rate

Patient responses per IRF by baseline disease

stage/involvement (ITT population)

Treatment group

ORR4 rate

difference

(95% CI)

Brentuximab vedotin

(N=64)

Physician’s choice

(N=64)

n (%) Total ORR4 ORR CR rate Total ORR4 ORR CR rate

MF 48 (75) 24 (50) 31 (65) 5 (10) 49 (77) 5 (10) 8 (16) 0 39.8 (19.9, 56.2)

Stage*

IA–IIA 15 (31) 6 (40) 8 (53) 1 (7) 18 (37) 4 (22) 5 (28) 0 17.8 (–16.6, 49.4)

IIB 19 (40) 12 (63) 13 (68) 3 (16) 19 (39) 1 (5) 3 (16) 0 57.9 (25.4, 80.9)

IIIA–IIIB 4 (8) 2 (50) 3 (75) 0 2 (4) 0 0 0 50.0 (–45.2, 98.7)

IVA 2 (4) 2 (100) 2 (100) 1 (50) 9 (18) 0 0 0 100.0 (14.9, 100)

IVB 7 (15) 2 (29) 4 (57) 0 0 NA NA NA NA

pcALCL 16 (25) 12 (75) 12 (75) 5 (31) 15 (23) 3 (20) 5 (33) 1 (7) 55.0 (19.7, 80.4)

Involvement

Skin only 9 (56) 8 (89) 8 (89) 4 (44) 11 (73) 3 (27) 5 (45) 1 (9) 61.6 (17.9, 88.3)

Extracutaneous 7 (44) 4 (57) 4 (57) 1 (14) 4 (27) 0 0 0 57.1 (–9.0, 93.2)The percentage shown in the total column describes the proportion of patients from that treatment group and the number of patients demonstrating ORR4, ORR, and CR is presented as a percentage of the figure shown

in the total column

*One patient in each arm had incomplete staging data and are not included in the table; one patient in the brentuximab vedotin arm had a PR, and one patient in the physician’s choice arm had no response

ITT, intent-to-treat; NA, not applicable

Brentuximab vedotin was superior to physician’s choice in terms of ORR4, ORR, and CR rate in MF patients across all

disease stages and in pcALCL patients with skin-only and extracutaneous disease

In both the brentuximab vedotin and physician's choice groups, the majority of patients presented with stage IA, IIA or

IIB disease and the majority of pcALCL patients presented with skin-only disease

Patient responses per IRF by baseline disease

stage/involvement (ITT population)

Treatment group

ORR4 rate

difference

(95% CI)

Brentuximab vedotin

(N=64)


(N=64)

n (%) Total ORR4 ORR CR rate Total ORR4 ORR CR rate

MF 48 (75) 24 (50) 31 (65) 5 (10) 49 (77) 5 (10) 8 (16) 0 39.8 (19.9, 56.2)

Stage*

IA–IIA 15 (31) 6 (40) 8 (53) 1 (7) 18 (37) 4 (22) 5 (28) 0 17.8 (–16.6, 49.4)

IIB 19 (40) 12 (63) 13 (68) 3 (16) 19 (39) 1 (5) 3 (16) 0 57.9 (25.4, 80.9)

IIIA–IIIB 4 (8) 2 (50) 3 (75) 0 2 (4) 0 0 0 50.0 (–45.2, 98.7)

IVA 2 (4) 2 (100) 2 (100) 1 (50) 9 (18) 0 0 0 100.0 (14.9, 100)

IVB 7 (15) 2 (29) 4 (57) 0 0 NA NA NA NA

pcALCL 16 (25) 12 (75) 12 (75) 5 (31) 15 (23) 3 (20) 5 (33) 1 (7) 55.0 (19.7, 80.4)

Involvement

Skin only 9 (56) 8 (89) 8 (89) 4 (44) 11 (73) 3 (27) 5 (45) 1 (9) 61.6 (17.9, 88.3)

Extracutaneous 7 (44) 4 (57) 4 (57) 1 (14) 4 (27) 0 0 0 57.1 (–9.0, 93.2)

Brentuximab vedotin was superior to physician’s choice in terms of ORR4, ORR, and CR rate in MF patients across all

disease stages and in pcALCL patients with skin-only and extracutaneous disease

In both the brentuximab vedotin and physician's choice groups, the majority of patients presented with stage IA, IIA or

IIB disease and the majority of pcALCL patients presented with skin-only disease

Patient responses per IRF by baseline TNMB stage

per investigator: MF

For patients with MF, ORR4 and ORR were superior with brentuximab vedotin versus physician’s

choice across subgroups defined by TNMB stage

*One patient in the physician’s choice arm had no biopsy performed to confirm visceral staging, and had no response; †One patient in the brentuximab vedotin arm had incomplete staging data, and had a PR; ‡One

patient in the physician’s choice arm had confirmed blood stage B1 at screening and B2 at baseline

Treatment group

Brentuximab vedotin

(N=64)


(N=64)

n (%) Total ORR4 ORR CR Total ORR4 ORR CR

MF 48 (75) 24 (50) 31 (65) 5 (10) 49 (77) 5 (10) 8 (16) 0

Skin*

T1 5 (10) 1 (20) 1 (20) 0 1 (2) 0 1 (100) 0

T2 13 (27) 7 (54) 10 (77) 1 (8) 20 (41) 4 (20) 4 (20) 0

T3 25 (52) 13 (52) 16 (64) 4 (16) 24 (49) 1 (4) 3 (13) 0

T4 5 (10) 3 (60) 4 (80) 0 4 (8) 0 0 0

Node

N0 25 (52) 14 (56) 18 (72) 4 (16) 23 (47) 2 (9) 5 (22) 0

N1–NX 23 (48) 10 (43) 13 (57) 1 (4) 26 (53) 3 (12) 3 (12) 0

Visceral*

M0 41 (85) 22 (54) 27 (66) 5 (12) 48 (98) 5 (10) 8 (17) 0

M1 7 (15) 2 (29) 4 (57) 0 0 NA NA NA

Blood†

B0 43 (90) 23 (53) 28 (65) 4 (9) 41 (84) 4 (10) 6 (15) 0

B1 4 (8) 1 (25) 2 (50) 1 (25) 7 (14) 1 (14) 2 (29) 0

B2‡ 0 NA NA NA 1 (2) 0 0 0

Patient responses per IRF by baseline TNMB stage

per investigator: pcALCL

Treatment group

Brentuximab vedotin

(N=64)


(N=64)

n (%) Total ORR4 ORR CR Total ORR4 ORR CR

pcALCL 16 (25) 12 (75) 12 (75) 5 (31) 15 (23) 3 (20) 5 (33) 1 (7)

Skin

T1 1 (6) 1 (100) 1 (100) 1 (100) 4 (27) 1 (25) 2 (50) 0

T2 3 (19) 3 (100) 3 (100) 1 (33) 5 (33) 0 1 (20) 0

T3 12 (75) 8 (67) 8 (67) 3 (25) 6 (40) 2 (33) 2 (33) 1 (17)

Node

N0 10 (63) 8 (80) 8 (80) 4 (40) 11 (73) 3 (27) 5 (45) 1 (9)

N1–NX 6 (38) 4 (67) 4 (67) 1 (17) 4 (27) 0 0 0

Visceral

M0 12 (75) 9 (75) 9 (75) 5 (42) 14 (93) 3 (21) 5 (36) 1 (7)

M1 4 (25) 3 (75) 3 (75) 0 1 (7) 0 0 0

For patients with pcALCL, ORR4 and ORR were higher with brentuximab vedotin versus physician’s

choice in patients with skin involvement, nodal involvement, and visceral involvement

Treatment group

Risk difference

(95% CI) P-value

Brentuximab

vedotin (N=64)

n (%)

Physician’s

choice (N=64)

n (%)

ORR4 39 (60.9) 5 (7.8) 53.1 (36.5, 67.2) <0.001

Best response per investigator

CR 12 (18.8) 0 18.8 (0.7, 35.9) <0.001

PR 32 (50.0) 14 (21.9) 28.1 ( – ) –

ORR 44 (68.8) 14 (21.9) 46.9 (31.7, 62.1) <0.001

SD 13 (20.3) 29 (45.3) –25.0 ( – ) –

PD 3 (4.7) 13 (20.3) –15.6 ( – ) –

updated analyses of treatment response and clinical benefit per investigator assessment after a

median follow-up of 33.9 months (data cut-off August 16, 2017)

ITT, intent-to-treat; PD, progressive disease; PR, partial response; SD, stable disease

Updated at 34 month follow up (ITT population)

Duration of response by diagnosis

DoR was much longer for patients with pcALCL receiving brentuximab vedotin (median DoR 25.5

months) than for patients with MF receiving brentuximab vedotin (median DoR 14.4 months)

Treatment group

Brentuximab vedotin (N=64) Physician’s choice (N=64)

MF

Number of patients, n (%) 48 (75) 49 (77)

Number of responders, n (%) 31 (65) 8 (16)

Median (95% CI) DoR, months 14.4 (8.5, 18.8) 18.3 (2.1, 18.4)

pcALCL

Number of patients, n (%) 16 (25) 15 (23)

Number of responders, n (%) 12 (75) 5 (33)

Median (95% CI) DoR, months 25.5 (9.5, 25.5) NE (NE, NE)

Treatment duration and follow-up status of

patients receiving brentuximab vedotin (MF and pcALCL)

SD, stable disease

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180

Time (weeks)

Dis

co

ntin

ue

d tre

atm

en

t fo

r re

aso

n o

the

r th

an

PD

(n=

51

)

Each row represents one unique patient; bar length represents treatment duration; bar color shows best overall response;

black lines show response duration following end of treatment; black lines with no symbol at the end shows no PD/death at

last assessment;*Patient response was not evaluable until 120 weeks (response assessment at 120 weeks showed PD).

No response assessment

SD

CR

Time of PD

Death

PD

PR

*

Median follow-up for PFS was 33.9m

With 46 and 51 patients having progressed (39 and 46 patients) or died (7 and 5 patients), respectively, median PFS

with brentuximab vedotin versus physician’s choice was 15.8 versus 3.6 months

Kaplan-Meier estimates demonstrated improved PFS rates with brentuximab vedotin versus physician’s choice at

1 year (63.9% vs 15.6%) and 2 years (28.8% vs 8.4%)

Progression-free survival Updated at 34 month follow up (ITT)

Time to next treatment (TTNT)

At a median follow-up of 33.9 months, 47 (73%) and 48 (75%) of patients in the brentuximab vedotin and

physician’s choice arms, respectively, had received ≥1 subsequent antineoplastic therapy

Median TTNT was significantly longer with brentuximab vedotin versus physician’s choice (14.2 vs 6.1 months; HR

0.335; 95% CI, 0.218–0.515; p<0.001)

In the brentuximab vedotin versus physician’s choice arms, the probability of patients not requiring subsequent

antineoplastic therapy was greater at 1 year (65.5% vs 15.3%) and 2 years (24.6% vs 4.4%) post-randomization

Pro

ba

bili

ty o

f su

bse

qu

en

t

antin

eo

pla

stic th

era

py

PFS vs Time to next treatment (TTNT)

Median follow-up of approx 34 months

median PFS with brentuximab vedotin versus physician’s choice was 15.8 versus 3.6 months

median TTNT with brentuximab vedotin versus physician’s choice was 14.2 versus 6.1 months

PFS rates with BV versus physician’s choice at 1 year (63.9% vs 15.6%) and 2 years (28.8% vs 8.4%)

TTNT rates with BV versus physician’s choice at 1 year (65.5% vs 15.3%) and 2 years (24.6% vs 4.4%)

Why a difference

– PFS does not capture symptoms (itch, pain)

– PFS does not capture transformation – early treatment before formal PFS*

– Tempo or severity of relapse can be different – is severity of relapse on BV worse? * - longer TTNT than PFS of 3m for PC

Do we need to consider these issues in an updated “Response criteria”

Median follow-up for OS was 33.9 months, median OS was not reached in either arm; OS was not

significantly different between arms (p=0.794)

Kaplan-Meier estimates demonstrated a higher OS rate with brentuximab vedotin versus

physician’s choice at 1 year (90.4% vs 76.6%), but not at 2 years (71.1% vs 72.6%)

Overall survival

Patient-reported QoL assessed by Skindex-29 questionnaire showed significantly greater

symptom reduction for patients receiving brentuximab vedotin versus physician’s choice

(mean maximum reduction –28.08% vs –8.62%; p<0.001)

QoL per changes in symptom domain by Skindex-29 questionnaire

CD30 expression: Non-transformed mycosis fungoides with some CD30 expression

• For example, between lesions

– In patients with MF, CD30 expression can vary from lesion to lesion,13 and so can

change simply because of intrapatient variability

Challenges in CD30 detection and quantification

*In IHC, methods and techniques may vary for tissue sampling, fixation, embedding, sectioning and

mounting, antigen retrieval, primary antibody, visualisation and interpretation7

1. Wasik MA, et al. Pathobiology 2013;80:252–8; 2. von Wasielewski R, et al. Am J Pathol 1997;151:1123–30;

3. Weisenburger DD, et al. Blood 2011;117:3402–8; 4. Stacchini A, et al. Am J Clin Pathol 2007;128:854–64;

5. Hu S, et al. Blood 2013;121:2715–24; 6. Willemze R, et al. Blood 2005;105:3768–85; 7. Taylor CR, Rudbeck L (eds).

Education guide: Immunohistochemical staining methods, 6th ed. Glostrup: Dako Demark, 2013; 8. Savage KJ, et al. Blood

2008;111:5496–504; 9. Piccaluga PP, et al. J Clin Oncol 2013;31:3019–25; 10. Delabie J, et al. Blood 2011;118:148–55;

11. Kuo T-T, et al. Int J Surg Pathol 2004;12:375–87; 12. Kim YH, et al. J Clin Oncol 2015;33:3750–8; 13. Kim YH, et al.

Poster presentation at the American Society of Clinical Oncology Annual Meeting 2017; abstract 7517.

• Prognostic value of CD30 expression is unclear: study results are conflicting5,8–11

• Prognostic relevance may be subtype specific5,8,9

• CD30 expression may impact on efficacy of anti-CD30 therapy,12 although variability in

CD30 expression in patients categorised as CD30+ (≥10%) did not seem to correlate with

response13

What is the relationship

between CD30

expression and

treatment efficacy?

Can CD30

expression change?

• Critical for reliability/reproducibility1

• No consensus on what defines CD30 positivity

– Typically 10–20% of cells, but differs between studies1–5

– >75% in pcALCL and LyP (Type A and C)6

• Quantitation methods vary2–4,7*

• Issue of staining non-tumour cells; dual staining is not often used

How can measurement

of CD30 expression be

standardised?

Assessment of CD30 expression and statistical analysis

Patients with MF had ≥2 skin biopsies from separate skin lesions obtained at screening (baseline)

CD30 expression was determined using an investigational IHC diagnostic test (Ventana Medical

Systems, Inc., Tucson, AZ, USA)

Results were assessed centrally by one pathologist; patients were scored CD30-positive and

eligible for enrollment if ≥1 biopsy had ≥10% CD30-positive lymphoid cells at any intensity above

background

Of all baseline* biopsies (≥2):

– CD30min = minimum CD30 expression score; CD30max = maximum CD30 expression score

Efficacy analyses (ORR4 and PFS) were conducted for patients with MF in the brentuximab

vedotin versus physician’s choice arms by 10% cut-off to assess differences in outcome in those

with at least

1 biopsy <10% CD30-positive (CD30min <10%) versus all biopsies ≥10% CD30-positive (CD30min

≥10%)

Assessment of outcomes by CD30 expression was carried out in 100/125 eligible MF patients in

ALCANZA

*(screening) visit closest to first dose date

Assessment of CD30 expression and statistical analysis

CD30min = 10%

CD30max = 90%

CD30min ≥10%

CD30,

10%

CD30,

35%

CD30,

90%

CD30,

10%

CD30, 0%

CD30,

5%

CD30,

10%

CD30,

90%

CD30min = 0%

CD30max = 90%

CD30min <10%

ORR4 with brentuximab vedotin across a broad range

of baseline CD30 expression scores

Achieved

Not achieved

Response lasting

≥4 months (N=50)

CD30min per patientBrentuximab vedotin

n/N (%)


n/N (%)

Difference

% (95% CI)

CD30min <10% 9/22 (40.9) 2/21 (9.5) 31.4 (2.8, 58.1)

CD30min ≥10% 16/28 (57.1) 3/29 (10.3) 46.8 (20.6, 67.0)

Baselin

e C

D30 e

xpre

ssio

n,

% p

ositiv

e

0

CD30maxCD30min

10% cut-off

for enrollment10

20

30

40

50

60

70

80

90

100

MF patients who achieved ORR4

Superior PFS with brentuximab vedotin versus

physician’s choice regardless of baseline CD30 expression

Time (months) from randomization

0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

Pro

ba

bili

ty o

f P

FS

Censored

Censored

Brentuximab vedotin


Baseline CD30min <10%

Brentuximab vedotin


Baseline CD30min ≥10%

Brentuximab

vedotin

Physician’s

choiceHR (95% CI)

CD30min <10%

N 22 21 –

Median PFS

(95% CI)

27.9

(8.6, 27.9)

2.3

(1.6, 3.5)

0.125

(0.044, 0.355)

Number of events 8 17 –

CD30min ≥10%

N 28 29 –

Median PFS

(95% CI)

17.2

(9.8, NE)

3.5

(2.1, 4.6)

0.176

(0.072, 0.432)

Number of events 8 19 –

Enrolled patients with MF,

N=100

NE, not estimable

Safety profile of brentuximab vedotin

unaffected by baseline CD30 expression

AEs, n/N (%)

Brentuximab vedotin

(N=50)


(N=49)

Any AE

CD30min <10% 22/22 (100) 20/21 (95)

CD30min ≥10% 28/28 (100) 23/28 (82)

Grade ≥3

CD30min <10% 11/22 (50) 12/21 (57)

CD30min ≥10% 10/28 (36) 9/28 (32)

Serious AE

CD30min <10% 7/22 (32) 9/21 (43)

CD30min ≥10% 8/28 (29) 5/28 (18)

Peripheral neuropathy

CD30min <10% 15/22 (68) 0/21 (0)

CD30min ≥10% 19/28 (68) 2/28 (7)

Enrolled patients with MF (safety population), N=99

CD30+ transformed mycosis fungoides?

Results being analyzed

IHC images provided by HM Prince

Acknowledgments

The authors would like to thank

– the patients who participated in this study and their

families

– other investigators and staff at all ALCANZA clinical

sites

– the members of the Independent Data Monitoring

Committee and Independent Review Committee

We acknowledge

– the significant scientific contribution by Igor

Espinoza-Delgado, MD who passed away

– Matthew Hallam and Jenny Wilkinson of FireKite, an

Ashfield company, part of UDG Healthcare plc, for

writing support during the development of these

slides, which was funded by Millennium

Pharmaceuticals, Inc., and complied with Good

Publication Practice 3 ethical guidelines1

ALCANZA investigatorsAustralia: Judith Trotman, David Joske, H. Miles Prince, Kerry Taylor, Ian D. Lewis

Austria: Constanze Jonak, Franz Trautinger

Belgium: Oliver Bechter (Pascal Wolter), Dominique Bron

Brazil: Vladmir Claudio C. de Lima, Jose Antonio Sanches Junior

Canada: Richard Klasa

France: Martine Bagot, Marie Beylot-Barry, Stephane Dalle, Michel D'Incan, Brigitte Dreno,

Florent Grange

Germany: Jan Nicolay, Rudolf Stadler, Michael Weichenthal, Marion Wobser, Chalid Assaf,

Carmen Loquai

Italy: Pietro Quaglino, Michele Spina, Pier Luigi Zinzani, Alberto Bosi, Pier Paolo Fattori

Poland: Aleksandra Grzanka, Jan Walewski

Spain: Andres Lopez-Hernandez, Pablo L. Ortiz-Romero, Jose Juan Rifon Roca, Silvana

Novelli Canales

Switzerland: Reinhard Dummer

United Kingdom: Timothy Illidge, Rod Johnson, Sean Whittaker (Stephen Morris), Pam

McKay, Julia Scarisbrick

United States: Madeleine Duvic, Tatyana Feldman, Oleg Akilov (Larisa Geskin), Steve

Horwitz, Youn H. Kim, Barbara Pro (Timothy Kuzel), Adam Lerner, Herbert Eradat, Lubomir

Sokol, David C. Fisher, Sarah Hughey

1. Battisti WP, et al. Ann Intern Med 2015;163:461–4

Clinical Activity with Brentuximab Vedotin in Cutaneous T .... Prince… · Disclosures Co-funded...

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Transcript of Clinical Activity with Brentuximab Vedotin in Cutaneous T .... Prince… · Disclosures Co-funded...